Novel Loci (EIF4A2, ADIPOQ, TPRG1) for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change (ΔTHR) among Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Heart Study (FHS) Offspring Cohort (OS).

Aims/hypothesis: Triglyceride (TG) /High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark. Methods: Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Results: Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (p=1.58e-9) for ΔTHR; this gene locus has been reported before influencing baseline THR levels. Our GWLS found evidence for a significant linkage with a logarithm of the odds (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families (pedigree-specific LODs>0.1), we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2/ADIPOQ-rs114108468, p=5e-6, MAF=1.8%; TPRG1-rs16864075, p=3e-6, MAF=8%; accounted for ~28% and ~29% of the linkage, respectively, and 57% jointly). While the former variant was associated with EIF4A2 (p=7e-5) / ADIPOQ (p=3.49e-2) RNA transcriptional levels, the latter variant was not associated with TPRG1 (p=0.23) RNA transcriptional levels. Replication in FHS OS observed modest effect of these loci on ΔTHR. Of 188 metabolites from 13 compound classes assayed in LLFS, we observed multiple metabolites (e.g., DG.38.5, PE.36.4, TG.58.3) that were significantly associated with the variants (p<3e-4). Conclusions: our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes selected for exceptional survival and healthy aging.

Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta-analyses: The Long Life Family Study.

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genome-wide association study (GWAS) p-values in 4182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of 1209 individuals. We identified 59 pleiotropic GWAS loci (p < 5 × 10-8) and 17 TWAS genes (Bonferroni-p < 2.73 × 10-6) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG, were associated with eGFR and sRAGE located within GWAS loci, lncRNA-KCNQ1OT1 and CACNA1A/CCDC130, respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer-promoter variants with kidney function-related phenotypes at p < 5 × 10-8. Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA-Europeans and TOPMed, suggesting better kidney function in healthy-aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and aging-related processes. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney- and aging-related signaling pathways.

Associations of Fecal Microbiota with Ectopic Fat in African Caribbean Men.

OBJECTIVE: The gut microbiome has been associated with visceral fat (VAT) in European and Asian populations; however, associations with VAT and with ectopic fats among African-ancestry individuals are not known. Our objective was to investigate cross-sectional associations of fecal microbiota diversity and composition with VAT and ectopic fat, as well as body mass index (BMI), among middle-aged and older African Caribbean men. METHODS: We included in our analysis n = 193 men (mean age = 62.2 ± 7.6 years; mean BMI = 28.3 ± 4.9 kg/m2) from the Tobago Health Study. We assessed fecal microbiota using V4 16s rRNA gene sequencing. We evaluated multivariable-adjusted associations of microbiota features (alpha diversity, beta diversity, microbiota differential abundance) with BMI and with computed tomography-measured VAT and ectopic fats (pericardial and intermuscular fat; muscle and liver attenuation). RESULTS: Lower alpha diversity was associated with higher VAT and BMI, and somewhat with higher pericardial and liver fat. VAT, BMI, and pericardial fat each explained similar levels of variance in beta diversity. Gram-negative Prevotellaceae and Negativicutes microbiota showed positive associations, while gram-positive Ruminococcaceae microbiota showed inverse associations, with ectopic fats. CONCLUSIONS: Fecal microbiota features associated with measures of general adiposity also extend to metabolically pernicious VAT and ectopic fat accumulation in older African-ancestry men.

Skeletal muscle adiposity is a novel risk factor for poor cognition in African Caribbean women.

OBJECTIVE: Skeletal muscle adiposity (myosteatosis) is recognized as a major risk factor for cardiometabolic diseases, and it increases with aging. The relationship of myosteatosis with cognitive impairment is unknown. METHODS: The association of calf myosteatosis (measured by computed tomography-derived skeletal muscle density; higher values indicate less myosteatosis) with cognitive function was examined among 626 African Caribbean women who were aged 40 to 84 years, a population highly vulnerable to increased myosteatosis. Cognition was assessed by the Digit Symbol Substitution Test (DSST), a test of information processing speed (higher scores indicate better performance). Linear regression was used to assess the association of muscle density with DSST. RESULTS: Adjusting for age, education, muscle area, BMI, hypertension, diabetes, cardiovascular event history, lifestyle factors, lipid-lowering medication use, and menopausal status, a one-SD lower muscle density was associated with a 1.69-point lower DSST score (p = 0.002). BMI, diabetes, and hypertension interactions were not statistically significant, suggesting that the main association was not moderated by overall obesity or cardiometabolic diseases. CONCLUSIONS: These findings suggest that greater myosteatosis is associated with slower information processing speed, an early indicator of cognitive impairment. Further studies are needed to establish this association in this and other populations using an expanded battery of cognitive tests with longitudinal follow-up and to identify the biological mechanisms underlying this relationship.

Exogenous exposures shape genetic predisposition to lipids, Alzheimer's, and coronary heart disease in the MLXIPL gene locus.

Associations of single nucleotide polymorphisms (SNPs) of the MLXIPL lipid gene with Alzheimer's (AD) and coronary heart disease (CHD) and potentially causal mediation effects of their risk factors, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), were examined in two samples of European ancestry from the US (22,712 individuals 587/2,608 AD/CHD cases) and the UK Biobank (UKB) (232,341 individuals; 809/15,269 AD/CHD cases). Our results suggest that these associations can be regulated by several biological mechanisms and shaped by exogenous exposures. Two patterns of associations (represented by rs17145750 and rs6967028) were identified. Minor alleles of rs17145750 and rs6967028 demonstrated primary (secondary) association with high TG (lower HDL-C) and high HDL-C (lower TG) levels, respectively. The primary association explained ~50% of the secondary one suggesting partly independent mechanisms of TG and HDL-C regulation. The magnitude of the association of rs17145750 with HDL-C was significantly higher in the US vs. UKB sample and likely related to differences in exogenous exposures in the two countries. rs17145750 demonstrated a significant detrimental indirect effect through TG on AD risk in the UKB only (ßIE = 0.015, pIE = 1.9 × 10-3), which suggests protective effects of high TG levels against AD, likely shaped by exogenous exposures. Also, rs17145750 demonstrated significant protective indirect effects through TG and HDL-C in the associations with CHD in both samples. In contrast, rs6967028 demonstrated an adverse mediation effect through HDL-C on CHD risk in the US sample only (ßIE = 0.019, pIE = 8.6 × 10-4). This trade-off suggests different roles of triglyceride mediated mechanisms in the pathogenesis of AD and CHD.

Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore.

BACKGROUND: The majority of hepatocellular carcinoma (HCC) cases occur in the presence of cirrhosis. Biomarkers of cirrhosis-associated immune dysfunction such as CD8+ T cell cytokines could aid HCC risk assessment. METHODS: CD8+ T cell cytokines were determined in pre-diagnostic serum in two studies including 315 HCC case-control pairs in the Shanghai Cohort Study (SCS) and 197 pairs in the Singapore Chinese Health Study (SCHS). Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with levels of five cytokines-soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1ß), and tumour necrosis factor alpha (TNF-α). RESULTS: sCD137 levels were significantly higher in HCC cases than controls in both cohorts (Ps < 0.001). Compared with the lowest quartile, multivariable-adjusted ORs (95% CI) of HCC for the highest sCD137 quartile were 3.79 (1.73, 8.30) in the SCS and 3.49 (1.44, 8.48) in the SCHS. The sCD137-HCC association was independent of hepatitis B seropositivity and follow-up time. No other cytokine was consistently associated with HCC risk. CONCLUSION: sCD137 was associated with higher risk of HCC in two studies nested in general population cohorts. sCD137 may be a long-term risk marker of HCC development.

Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end-products using correlated meta-analyses: The Long Life Family Study (LLFS).

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGE). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined genomewide association study (GWAS) p -values in 4,182 individuals (age range: 24-110) from the Long Life Family Study (LLFS). We also conducted transcriptome-wide association studies (TWAS) on whole blood in a subset of 1,209 individuals. We identified 59 pleiotropic GWAS loci ( p <5×10 -8 ) and 17 TWAS genes (Bonferroni- p <2.73×10 -6 ) for eGFR traits and sRAGE. TWAS genes, LSP1 and MIR23AHG , were associated with eGFR and sRAGE located within GWAS loci, lncRNA- KCNQ1OT1 and CACNA1A/CCDC130 , respectively. GWAS variants were eQTLs in the kidney glomeruli and tubules, and GWAS genes predicted kidney carcinoma. TWAS genes harbored eQTLs in the kidney, predicted kidney carcinoma, and connected enhancer-promoter variants with kidney function-related phenotypes at p <5×10 -8 . Additionally, higher allele frequencies of protective variants for eGFR traits were detected in LLFS than in ALFA-Europeans and TOPMed, suggesting better kidney function in healthy-aging LLFS than in general populations. Integrating genomic annotation and transcriptional gene activity revealed the enrichment of genetic elements in kidney function and kidney diseases. The identified pleiotropic loci and gene expressions for eGFR and sRAGE suggest their underlying shared genetic effects and highlight their roles in kidney- and aging-related signaling pathways.

Replacing sedentary time with light activity was associated with less adiposity across several depots in African ancestry men.

OBJECTIVE: The aim of this study was to determine whether displacement of sedentary time with activity was cross-sectionally associated with less adiposity among Black Caribbean men in the Tobago Health Study. METHODS: Objectively assessed activity was categorized as sedentary (< 1.5 metabolic equivalents; METs), light (≥ 1.5 to < 3.0 METs), or moderate-to-vigorous (≥ 3.0 METs) using the SenseWear Pro armband. Computed tomography scans of the chest, abdomen, liver, and thigh were used to assess subcutaneous and ectopic adipose tissue. The isotemporal substitution framework paired with linear regression was used to examine associations between activity and adiposity adjusting for age, height, total awake time, and multiple comparisons. RESULTS: On average, participants (n = 271) were 63 years old with 11.2 h/d of sedentary behavior, 4.5 h/d of light activity, and 54 min/d of moderate-to-vigorous activity. Replacing sedentary time with light activity was cross-sectionally associated with lower volume and higher density of abdominal and thigh subcutaneous adiposity, visceral adiposity, abdominal and thigh intermuscular adiposity, and pericardial adiposity and higher liver attenuation (p values ≤ 0.0001). CONCLUSIONS: Displacement of sedentary time with light activity was associated with less adiposity among this Black Caribbean cohort. Interventions focused on increasing light activity may be easier to maintain than higher intensity interventions and thus may be more successful at reducing adiposity.

Association of leukocyte telomere length with perceived physical fatigability.

BACKGROUND: Leukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relation to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adjusting for chronological age. METHODS: Two generations of participants (N = 1997; 309 probands, 1688 offspring) were from the Long Life Family Study (age = 73.7 ± 10.4, range 60-108, 54.4 % women), a longitudinal cohort study of aging. LTL was assayed at baseline. Perceived physical fatigability was measured 8.0 ± 1.1 years later using the validated, self-administered 10-item Pittsburgh Fatigability Scale (PFS, 0-50, higher scores = greater fatigability). Generalized estimating equations were generated to model the association between LTL and PFS Physical scores. RESULTS: Prevalence of greater physical fatigability (PFS scores≥15) was 41.9 %. Using generalized estimating equations, a one kilobase pair shorter LTL was associated with higher PFS Physical scores (ß = 1.8, p < .0001), accounting for family structure, and adjusting for field center, follow-up time, sex, and follow-up body mass index, physical activity, and chronic health conditions. When age was included as a covariate, the association was fully attenuated (ß = 0.1, p = .78). CONCLUSION: LTL may provide an alternative method for estimating an individual's lifetime exposure to chronic stressors, but does not appear to provide additional information not captured by chronological age. Further research is needed to characterize the interaction between age, LTL, and perceived fatigability, and develop a method of identifying individuals at risk for deleterious aging.

Physical resilience after a diagnosis of cardiovascular disease among offspring of long-lived siblings.

Health benefits of longevity-enriched families transmit across generations and a lower incidence of cardiovascular diseases (CVD) have been shown to contribute to this phenomenon. In the current study, we investigated whether the offspring of long-lived siblings also have better survival after a CVD diagnosis compared to matched controls, i.e., are they both robust and resilient? Offspring of long-lived siblings were identified from three nationwide Danish studies and linked to national registers. Offspring with first diagnosis of acute myocardial infarction, chronic ischemic heart disease, heart failure or cerebrovascular disease between 1996 and 2011 were included and matched with two controls from the Danish population on sex, year of birth and diagnosis, and type of CVD. Stratified Cox proportional-hazards models on the matching data were performed to study 10-year overall survival. A total of 402 offspring and 804 controls were included: 64.2% male with a median age at diagnosis of 63.0. For offspring and controls, overall survival was 73% and 65% at 10 years from diagnosis, respectively. Offspring of long-lived siblings had a significantly better survival than controls, and this association was slightly attenuated after controlling for marital status, medication and Charlson Comorbidity Index score simultaneously. This study suggested that offspring of long-lived siblings not only show lower CVD incidence but also a better survival following CVD diagnosis compared to matched population controls. The higher biological resilience appears to be a universal hallmark of longevity-enriched families, which makes them uniquely positioned for studying healthy aging and longevity mechanisms. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-021-00641-7.

NAFLD polygenic risk score and risk of hepatocellular carcinoma in an East Asian population.

It is difficult to identify people with nonalcoholic fatty liver disease (NAFLD) who are at high risk for developing hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat (HFC-PRS) derived from non-Asians has been reported to be associated with HCC risk in European populations. However, population-level data of this risk in Asian populations are lacking. Utilizing resources from 24,333 participants of the Singapore Chinese Health Study (SCHS), we examined the relationship between the HFC-PRS and HCC risk. In addition, we constructed and evaluated a NAFLD-related PRS (NAFLD-PRS) with HCC risk in the SCHS. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence with both HFC-PRS and NAFLD-PRS. The HFC-PRS and NAFLD-PRS were highly correlated (Spearman r = 0.79, p < 0.001). The highest quartiles of both the HFC-PRS and the NAFLD-PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared with their respective lowest quartile. Conclusion: The PRS for hepatic fat content or NAFLD may be useful for assessing HCC risk in both Asian and European populations. The findings of this and prior studies support a potential causal role of genetically determined NAFLD in HCC development.

Relative associations of abdominal and thigh compositions with cardiometabolic diseases in African Caribbean men.

BACKGROUND: Regional body compositions are differentially associated with cardiometabolic risk factors. Simultaneous inclusion of both upper and lower body composition predictors in models is not often done, and studies which do include both measures (1) tend to exclude some tissue(s) of potential metabolic relevance, and (2) have used study populations with underrepresentation of individuals with African ancestries. Further, most body composition analyses do not employ compositional data analytic approaches, which may result in spurious associations. OBJECTIVE: The objective of this analysis was to assess associations of abdominal and thigh adipose (AT) and muscle tissues with hypertension and type 2 diabetes using compositional data analytic methods. RESEARCH DESIGN AND METHODS: This cross-sectional analysis included 610 African Caribbean men (median age: 62 years; mean BMI: 27.8 kg/m2). Abdominal (three components: subcutaneous [ASAT] and visceral [VAT] AT, 'other' abdominal tissue) and mid-thigh (four components: subcutaneous and intermuscular AT, muscle, bone) compositions were measured by computed tomography; additive log ratio transformations were applied to each composition. Regression models were used to simultaneously assess associations of abdominal and thigh component ratios with continuous risk factors (blood pressures, fasting glucose and insulin, HOMA-IR) and disease categories. RESULTS: A two-fold increase in ASAT:'Other' ratio was associated with higher continuous risk factors and with odds of being in a higher hypertension (OR: 1.77, 95%CI: 1.10-2.84) or diabetes (OR: 1.81, 95%CI: 1.06-3.10) category. A two-fold increased VAT ratio was only associated with higher log-insulin and log-HOMA-IR (ß = 0.10, p < 0.05 for both), while a two-fold increased thigh muscle:bone ratio was associated with a lower diabetes category (OR: 0.37, 95%CI: 0.14-1.01). CONCLUSIONS: These findings support ASAT as a significant driver of cardiometabolic disease in African Ancestry populations, independent of other abdominal and thigh tissues.

Pleiotropic effects between cardiovascular disease risk factors and measures of cognitive and physical function in long-lived adults.

Cardiovacular disease (CVD) is the leading cause of death among older adults and is often accompanied by functional decline. It is unclear what is driving this co-occurrence, but it may be behavioral, environmental and/or genetic. We used a family-based study to estimate the phenotypic and shared genetic correlation between CVD risk factors and physical and cognitive functional measures. Participants (n = 1,881) were from the Long Life Family Study, which enrolled families based on their exceptional longevity (sample mean age = 69.4 years, 44% female). Cardiovascular disease risk factors included carotid vessel measures [intima-media thickness and inter-adventitial diameter], obesity [body mass index (BMI) and waist circumference], and hypertension [systolic and diastolic blood pressures]. Function was measured in the physical [gait speed, grip strength, chair stand] and cognitive [digital symbol substitution test, retained and working memory, semantic fluency, and trail making tests] domains. We used SOLAR to estimate the genetic, environmental, and phenotypic correlation between each pair adjusting for age, age2, sex, field center, smoking, height, and weight. There were significant phenotypic correlations (range |0.05-0.22|) between CVD risk factors and physical and cognitive function (all P < 0.05). Most significant genetic correlations (range |0.21-0.62|) were between CVD risk factorsand cognitive function, although BMI and waist circumference had significant genetic correlation with gait speed and chair stand time (range |0.29-0.53|; all P < 0.05). These results suggest that CVD risk factors may share a common genetic-and thus, biologic-basis with both cognitive and physical function. This is particularly informative for research into the genetic determinants of chronic disease.

Association of physical activity with blood pressure in African ancestry men.

This study tested the association of objectively measured physical activity with blood pressure and hypertension in African Caribbean men, an understudied population segment known to be at high-risk for cardiovascular disease (CVD) which has low levels of high-exertion physical activity. Men (N = 310) were from the Tobago Health Study and aged 50-89 years. Systolic (SBP) and diastolic (DBP) blood pressures were measured using an automated device, and hypertension was defined as SBP ≥ 140 mmHg, DBP ≥ 90 mmHg, or current use of antihypertensive medication. Physical activity was measured using the SenseWear Pro armband (SWA) and consisted of daily time engaged in sedentary behavior (SB), light physical activity (LPA), and moderate to vigorous activity (MVPA), as well as daily step count. Multiple regression analyses using the isotemporal substitution framework were used to test for associations between activity and blood pressures. Models were adjusted in stages for SWA wear time, age, antihypertensive medication use, alcohol consumption, smoking, diabetes, CVD, family history of hypertension, salt intake, and adiposity. Replacement of SB with LPA was associated with lower SBP adjusted for wear time (ß = -0.84, p < 0.05), but attenuated after adjustment for age. Replacement of SB with LPA was associated with lower DBP (ß = -0.50) and lower odds of hypertension (OR = 0.88), adjusted for wear time and age (both p < 0.05). All model associations of replacement of SB with LPA were stronger when restricted to men not taking antihypertensive medications, regardless of their hypertension status. These results support the strategy of increasing light physical activity for blood pressure management in high-risk Afro-Caribbean men.

Heterogeneity of the Predictive Polygenic Risk Scores for Coronary Heart Disease Age-at-Onset in Three Different Coronary Heart Disease Family-Based Ascertainments.

BACKGROUND: Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-at-onset, sex, and family health history differ significantly. METHODS: Our study included 3 family-based ascertainments: LLFS (Long Life Family Study, NIndividuals=4572), which represents a low CHD risk, and Family Heart Study, which consists of randomly selected families (FamHS-random, NIndividuals=1806), and high CHD risk families (FamHS-high risk, NIndividuals=2301). We examined the effects of PRS, sex, family ascertainment, PRS interaction with sex (PRS*sex) and with family ascertainment (PRS*LLFS and PRS*FamHS-high risk) on CHD, corrected for traditional cardiovascular risk factors using Cox proportional hazard regression models. RESULTS: Healthy-aging LLFS presented ≈17 years delayed for CHD age-at-onset compared with FamHS-high risk (P<1.0×10-4). Sex-specific association (P<1.0×10-17) and PRS*sex (P=2.7×10-3) predicted prevalent CHD. CHD age-at-onset was associated with PRS (hazard ratio [HR], 1.57; P=1.3×10-5), LLFS (HR, 0.54; P=2.6×10-5), and FamHS-high risk (HR, 2.86; P=6.70x10-15) in men, and with PRS (HR, 1.76; P=7.70×10-3), FamHS-high risk (HR, 4.88; P=8.70×10-10), and PRS×FamHS-high risk (HR, 0.61; P=3.60×10-2) in women. In the PRS extreme quartile distributions, CHD age-at-onset was associated (P<0.05) with PRS, FamHS-high risk, and PRS interactions with both low and high CHD risk families for women. For men, the PRS quartile results remained similar to the whole distribution. CONCLUSIONS: Differences in CHD family-based ascertainments show evidence of PRS interacting with sex to predict CHD risk. In women, CHD age-at-onset was associated with PRS, CHD family history, and interactions of PRS with family history. In men, PRS and CHD family history were the major effects on the CHD age-at-onset. Understanding the heterogeneity of risks associated with CHD end points at both the personal and familial levels may shed light on the underlying genetic effects influencing CHD and lead to more personalized risk prediction.

Genetic association analysis of the cardiovascular biomarker: N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP).

BACKGROUND: NT-proBNP is a biomarker of cardiovascular disease (CVD). Little is known about the heritability and genetic variants associated with NT-proBNP. Therefore, we estimated the heritability of and examined genetic associations of SNPs in the BNP gene region with circulating NT-proBNP and prevalent CVD in 4,331 participants from the Long Life Family Study (LLFS). METHODS AND RESULTS: Genotypes of 10 SNPs from the NPPB and NPPA regions that encode BNP and A-type natriuretic peptide, respectively, were tested for association with NT-proBNP and prevalent cardiovascular disease and risk factors. We performed analyses using the Sequential Oligogenic Linkage Analysis (SOLAR) program to account for family relatedness, and adjusted all models for age, sex, and field center. The mean age of the LLFS was 69.8 years (range 24-110) with 55.4% females. NT-proBNP was significantly heritable (h2 = 0.21; P = 4x10-14), and the minor alleles of rs632793 (p<0.001) and rs41300100 (p = 0.05) were independently associated with higher serum NT-proBNP levels. Additionally, the minor allele of rs632793 was significantly and consistently associated with lower prevalent CVD, including blood pressures, independent of NT-proBNP level (all P<0.05). Results for prevalent CVD, but not NT-proBNP levels, showed significant interaction by familial generation. CONCLUSION: In this family-based study of subjects with exceptional longevity, we identified several allelic variants in the BNP gene region associated with NT-pro-BNP levels and prevalent CVD.

A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations.

Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I2 index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10-4 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10-4 ) and 7q31 (WNT16, p = 2.96 × 10-5 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10-4 ), 11q14 (DCDC5, p < 5.35 × 10-5 ), and 17p13 (SMG6, p < 6.78 × 10-5 ) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10-2 ), MBL2 (p = 4.09 × 10-2 ), MEPE (p = 3.15 × 10-2 ), SLC25A13 (p = 3.03 × 10-2 ), STARD3NL (p = 3.35 × 10-2 ), and TNFRSF11A (p = 3.18 × 10-3 ) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants. © 2020 American Society for Bone and Mineral Research (ASBMR).

Relationship Between Serum IGF-1 and BMI Differs by Age.

BACKGROUND: Serum levels of insulin-like growth factor 1 (IGF-1) and body mass index (BMI) are both associated with susceptibility to age-related diseases. Reports on the correlation between them have been conflicting, with both positive to negative correlations reported. However, the age ranges of the participants varied widely among these studies. METHODS: Using data on 4241 participants (aged 24-110) from the Long Life Family Study, we investigated the relationship between IGF-1 and BMI by age groups using regression analysis. RESULTS: When stratified by age quartile, the relationship between IGF-1 and BMI varied: in the first quartile (Q1, 20-58 years) the relationship was negative (ß = -0.2, p = .002); in Q2 (58-66 years) and Q3 (67-86 years) the relationship was negative (ß = -0.07, ß = -0.01, respectively) but nonsignificant; and in Q4 (87-110 years) the relationship was positive (ß = 0.31, p = .0002). This pattern did not differ by sex. We observed a similar age-related pattern between IGF-1 and BMI among participants in the third National Health and Nutritional Examination Survey. CONCLUSIONS: Our results that the relationship between IGF-1 and BMI differs by age may explain some of the inconsistency in reports about their relationship and encourage additional studies to understand the mechanisms underlying it.

Hepatic and Skeletal Muscle Adiposity Are Associated with Diabetes Independent of Visceral Adiposity in Nonobese African-Caribbean Men.

Background: Adipose tissue (AT) around and within non-AT organs (i.e., ectopic adiposity) is emerging as a strong risk factor for type 2 diabetes (T2D). Not known is whether major ectopic adiposity depots, such as hepatic, skeletal muscle, and pericardial adiposity (PAT), are associated with T2D independent of visceral adiposity (VAT). More data are particularly needed among high-risk nonobese minority populations, as the race/ethnic gap in T2D risk is greatest among nonobese. Methods: Thus, we measured several ectopic adiposity depots by computed tomography in 718 (mean age = 64 years) African-Caribbean men on the Island of Tobago overall, and stratified by obesity (obese N = 187 and nonobese N = 532). Results: In age, lifestyle risk factors, health status, lipid-lowering medication intake, body mass index and all other adiposity-adjusted regression analyses, and hepatic and skeletal muscle adiposity were associated with T2D among nonobese men only (all P < 0.05), despite no association between VAT and PAT and T2D. Conclusions: Our results support the "ectopic fat syndrome" theory in the pathogenesis of T2D among nonobese African-Caribbean men. Longitudinal studies are needed to clarify the independent role of ectopic adiposity in T2D, and to identify possible biological mechanisms underlying this relationship, particularly in high-risk African ancestry and other nonwhite populations.

Wnt Pathway Gene Expression Is Associated With Arterial Stiffness.

Background Animal and in vitro experiments implicate the Wnt pathway in cardiac development, fibrosis, vascular calcification, and atherosclerosis, but research in humans is lacking. We examined peripheral blood Wnt pathway gene expression and arterial stiffness in 369 healthy African ancestry men (mean age, 64 years). Methods and Results Gene expression was assessed using a custom Nanostring nCounter gene expression panel (N=43 genes) and normalized to housekeeping genes and background signal. Arterial stiffness was assessed via brachial-ankle pulse-wave velocity. Fourteen Wnt genes showed detectable expression and were tested individually as predictors of pulse-wave velocity using linear regression, adjusting for age, height, weight, blood pressure, medication use, resting heart rate, current smoking, alcohol intake, and sedentary lifestyle. Adenomatous polyposis coli regulator of Wnt signaling pathway (APC), glycogen synthase kinase 3ß (GSK3B), and transcription factor 4 (TCF4) were significantly associated with arterial stiffness (P<0.05 for all). When entered into a single model, APC and TCF4 expression remained independently associated with arterial stiffness (P=0.04 and 0.003, respectively), and each explained ≈3% of the variance in pulse-wave velocity. Conclusions The current study establishes a novel association between in vivo expression of the Wnt pathway genes, APC and TCF4, with arterial stiffness in African ancestry men, a population at high risk of hypertensive vascular disease.